Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases

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Abstract

Background

This study aims to provide genetic diagnoses for 30 cases of fetal skeletal dysplasia, and a molecular basis for the future prenatal diagnosis of fetal skeletal dysplasia.

Methods

A total of 30 cases of fetal skeletal dysplasia detected with ultrasound between January 2014 and June 2017 were analyzed. Among these fetuses, 15 fetuses had local skeletal malformations, while 15 fetuses had short limb malformations. Samples of fetal umbilical cord blood, amniotic fluid, and/or aborted tissue were collected from all cases. Karyotyping, whole genome sequencing, and targeted next-generation sequencing of skeletal disease-related pathogenic genes were performed, as needed. Blood samples were taken from the parents for verification using Sanger sequencing.

Results

Among the 30 cases of fetal skeletal dysplasia, two cases were diagnosed with trisomy 18. However, none of these cases were identified with any microdeletions or microreplications associated with skeletal dysplasia. Among the 28 chromosomally normal cases with fetal skeletal dysplasia, 21 cases were detected with mutations in genes related to skeletal diseases. Furthermore, collagen gene mutations were detected in six fetuses with short limb malformations, while heterozygous disease-causing mutations in the fibroblast growth factor receptor 3 ( FGFR3) gene were detected in seven fetuses. The remaining fetuses carried mutations in other various genes, including tumor protein p63 ( TP63), cholestenol delta-isomerase ( EBP), cholinergic receptor nicotinic gamma subunit ( CHRNG), filamin B ( FLNB), and SRY-box 9 ( SOX9). Three compound heterozygous mutations in CHRNG, COL11A2 and SOX9 were carried by phenotypically healthy parents.

Conclusion

Targeted next-generation sequencing can significantly improve the prenatal diagnoses of fetal skeletal dysplasia, providing parents with more precision medicine, and improved genetic counseling.

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Most cited references 40

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Nosology and Classification of Genetic Skeletal Disorders: 2010 Revision

Matthew Warman, Valerie Cormier-Daire, Christine Hall … (2011)

Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology. © 2011 Wiley-Liss, Inc.

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The birth prevalence rates for the skeletal dysplasias.

Eduardo Castilla, Gunter Hans-Filhio, Iêda M Orioli (1986)

This study was undertaken to establish the prevalence rates at birth of the skeletal dysplasias that can be recognised in the perinatal period. Using the data base of the Latin-American Collaborative Study of Congenital Malformations (ECLAMC), for the years 1978 to 1983, on 349 470 births (live and stillbirths), a crude prevalence rate of 2.3/10 000 was observed. However, several indications of under-registration suggest that the real value is about twice that observed. The most frequent types of skeletal dysplasia were achondroplasia, with a prevalence rate between 0.5 and 1.5/10 000 births, the thanatophoric dysplasia/achondrogenesis group (0.2 and 0.5/10 000 births), and osteogenesis imperfecta (0.4/10 000 births). The mutation rate for autosomal dominant achondroplasia was estimated at between 1.72 and 5.57 X 10(-5) per gamete per generation.

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Achondroplasia is defined by recurrent G380R mutations of FGFR3.

G A Bellus, T Hefferon, R I Ortiz de Luna … (1995)

Genomic DNA from 154 unrelated individuals with achondroplasia was evaluated for mutations in the fibroblast growth factor receptor 3 (FGFR3) transmembrane domain. All but one, an atypical case, were found to have a glycine-to-arginine substitution at codon 380. Of these, 150 had a G-to-A transition at nt 1138, and 3 had a G-to-C transversion at this same position. On the basis of estimates of the prevalence of achondroplasia, the mutation rate at the FGFR3 1138 guanosine nucleotide is two to three orders of magnitude higher than that previously reported for tranversions and transitions in CpG dinucleotides. To date, this represents the most mutable single nucleotide reported in the human genome. The homogeneity of mutations in achondroplasia is unprecedented for an autosomal dominant disorder and may explain the relative lack of heterogeneity in the achondroplasia phenotype.

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Author and article information

Contributors

Qing-Qing Wu: +86 10 52276435 , wuqq2007@163.com

Journal

Journal ID (nlm-ta): Diagn Pathol

Journal ID (iso-abbrev): Diagn Pathol

Title: Diagnostic Pathology

Publisher: BioMed Central (London )

ISSN (Electronic): 1746-1596

Publication date (Electronic): 13 July 2019

Publication date PMC-release: 13 July 2019

Publication date Collection: 2019

Volume: 14

Electronic Location Identifier: 76

Affiliations

[1 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Department of Obstetrics, Beijing Obstetrics and Gynecology Hospital, , Capital Medical University, ; Beijing, 100026 China

[2 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Department of Ultrasound, Beijing Obstetrics and Gynecology Hospital, , Capital Medical University, ; Beijing, 100026 China

[3 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Department of Radiology, Beijing Obstetrics and Gynecology Hospital, , Capital Medical University, ; No. 251 of Yaojia Yuan Street, Chaoyang District, Beijing, 100026 China

Article

Publisher ID: 853

DOI: 10.1186/s13000-019-0853-x

PMC ID: 6626426

PubMed ID: 31299979

SO-VID: 67fe940e-59ea-47e5-a2af-2beafc38741b

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 April 2019

Date accepted : 3 July 2019

Funding

Funded by: National Key Research and Development Program of China

Award ID: 2016YFC1000104

Funded by: Beijing Municipal Administration Hospital Ascent Plan

Award ID: DFL20151302

Funded by: Beijing Municipal Science and Technology Commission

Award ID: Z161100000116089

Funded by: Capital Health Research and Development of Special

Award ID: 2014-2-2113

Custom metadata

ScienceOpen disciplines: Pathology

Keywords: fetal skeletal dysplasia,chromosomes,targeted next-generation sequencing,whole genome sequencing,prenatal diagnosis

Data availability:

ScienceOpen disciplines: Pathology

Keywords: fetal skeletal dysplasia, chromosomes, targeted next-generation sequencing, whole genome sequencing, prenatal diagnosis

Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases

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Abstract

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Methods

Results

Conclusion

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Most cited references 40

Nosology and Classification of Genetic Skeletal Disorders: 2010 Revision

The birth prevalence rates for the skeletal dysplasias.

Achondroplasia is defined by recurrent G380R mutations of FGFR3.

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